In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. Currently, a PI3K/mTOR inhibitor is being evaluated in human head/neck carcinoma cells lines. Impressive radiosensitization by the inhibitor is observed in vitro and in vivo. Treatment of cells with this inhibitor resulted in inhibition of radiation-induced DNA damage repair. The results of these pre-clinical study will provide the necessary information to consider a clinical human trial with this agent as a radiation sensitizer. Preliminary studies are underway with a novel HSP90 inhibitor as a potential radiation sensitizer. Significant in vitro radiation dose modification factors have been observed with this agent and xenograft studies are ongoing. This agent also has potential of being translated into human clinical trials. We continue to evaluate a number of metabolic inhibitors as radiation modifiers under the working hypothesis that inhibition of metabolism (for example, decreased ATP production) will diminish the repair of radiation-induced DNA damage. A Glut1 inhibitor (STF-31) has been identified as a significant radiation modifier. With respect to normal tissue response to radiation, we found rapamycin protects against radiation-induced oral mucositis in part by preventing radiation induced stem cell senescence. It was also demonstrated that mice that express a Smad7 transgene were resistant to radiation-induced mucositis by repressing activation of the TGF-beta signaling pathway. Topical application of Smad7 protein conjugated with cell-permeable Tat tag showed prophylatic and therapeutic effects on radiation-induced oral mucositis in mice. Oral mucositis is a common toxicity associated with the chemoradiation (cisplatin combined with fractionated radiation) treatment of head and neck cancers. Tempol also protects against chemoradiation-induced mucositis yet does not alter chemoradiation with respect to tumor regrowth delay. Collectively we have identified a number of pre-clinical approaches to initiate human radiation oncology clinical trials for protection against radiation-induced mucositis.